1) Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is transmissible through iatrogenic routes due to abundant infectious prions (PrPSc) in the central nervous system (CNS). Some epidemiological studies have associated sCJD risk with non-CNS surgeries. Here, we explored the potential prion-seeding activity and infectivity of skin from sCJD patients. Autopsy or biopsy skin samples from 38 patients 21 sCJD, 2 variant CJD (vCJD), and 15 non-CJD were analyzed by Western blotting and real-time quaking-induced conversion (RT-QuIC) for PrPSc. Skin samples from two patients were further examined for prion infectivity by bioassay using two lines of humanized transgenic mice. Western blotting revealed dermal PrPSc in one of five deceased sCJD patients and one of two vCJD patients. However, the more sensitive RT-QuIC assay detected prion-seeding activity in skin from all 23 CJD decedents but no non-CJD control individuals, including those with other neurological conditions, during blinded testing. Although sCJD patient skin contained 103-105 fold lower prion-seeding activity than did sCJD patient brain tissue, all twelve mice from two transgenic mouse lines inoculated with sCJD skin homogenates from two sCJD patients succumbed to prion disease within 564 days after inoculation. Our study demonstrates that the skin of sCJD patients contains both prion-seeding activity and infectivity, which raises concerns about the potential for iatrogenic sCJD transmission via skin. 2) The diagnosis and treatment of synucleinopathies such as Parkinson disease and dementia with Lewy bodies would be aided by the availability of assays for the pathogenic disease-associated forms of -synuclein (SynD) that are sufficiently sensitive, specific, and practical for analysis of accessible diagnostic specimens. Two recent SynD seed amplification tests have provided the first prototypes for ultrasensitive and specific detection of SynD in patients cerebrospinal fluid. These prototypic assays require 5-13 days to perform. Here, we describe an improved -synuclein real time quaking-induced conversion (Syn RT-QuIC) assay that has similar sensitivity and specificity to the prior assays, but can be performed in 1-2 days with quantitation. Blinded analysis of cerebrospinal fluid from 29 synucleinopathy cases 12 Parkinsons and 17 dementia with Lewy bodies and 31 non-synucleinopathy controls, including 16 Alzheimers cases, yielded 93% diagnostic sensitivity and 100% specificity for this test so far. End-point dilution analyses allowed quantitation of relative amounts of SynD seeding activity in cerebrospinal fluid samples, and detection in as little as 0.2 L. These results confirm that SynD seeding activity is present in cerebrospinal fluid. We also demonstrate that it can be rapidly detected, and quantitated, even in early symptomatic stages of synucleinopathy.